Deposition of ss-amyloid (Ass) in the cerebral vessels (cerebral amyloid angiopathy or CAA) is a major cause of hemorrhagic stroke, a contributor to vascular cognitive impairment, and a complicating factor in attempts to develop anti-amyloid immunotherapies. Current methods for detecting CAA during life are focused on identifying CAA-associated hemorrhages, typically after major hemorrhagic stroke has occurred. Growing evidence (including the high prevalence of lobar microbleeds in the general elderly population) suggests that advanced CAA is extremely common even in the absence of hemorrhagic stroke. The current proposal seeks to establish the early diagnosis of advanced CAA by validating and applying novel in vivo detection methods for individuals without hemorrhagic stroke. Preliminary data support three candidate detection methods: 1) increased retention of the amyloid ligand Pittsburgh Compound B (PiB) in an occipital-predominant pattern, 2) reduction of cerebrospinal fluid concentrations of the ss-amyloid Ass40 and Ass42 peptides, and 3) blunting of cerebrovascular reactivity to visual stimulation. We will validate these three approaches in two groups of patients with well established diagnoses of advanced CAA: sporadic patients with multiple lobar cerebral microbleeds recruited at Massachusetts General Hospital (Specific Aim 1) and familial patients genetically diagnosed with Dutch-type hereditary CAA recruited at Leiden University Medical Center (Specific Aim 2). Based on the diagnostic cut-points established in these two patients groups, we will then proceed to apply the detection methods to asymptomatic population-based subjects with strictly lobar microbleeds identified by the Rotterdam Scan Study (Specific Aim 3). Each of the three study groups will consist of 20 case subjects and 20 similar aged control subjects from the same site. Receiver operator characteristic techniques will be used to establish optimum methods for distinguishing CAA cases from non-CAA controls, applying results from the two patient groups with established CAA to the population-based Rotterdam Scan subjects where the presence of advanced CAA remains unknown. The three study populations represent the largest and most thoroughly characterized groups of sporadic CAA patients (Massachusetts General Hospital), hereditary CAA patients (Leiden University Medical Center) and population-based subjects scanned by MRI methods optimized for microbleed detection (Rotterdam Scan Study). This proposal also builds on the Principal Investigator's considerable success in developing a range of novel tools for characterizing CAA during life. Successful completion of the proposed studies will have potentially major impact on the fields of hemorrhagic stroke, vascular cognitive impairment, and Ass immunotherapy, by providing new information on an individual's risk of future hemorrhage, defining the true contribution of CAA to age-related cognitive decline, and possibly yielding new safety markers for anti-amyloid immunotherapy.